Materials Today Chemistry 13 (2019) 34e48

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Materials Today Chemistry

journal homepage: www.journals.elsevier.com/materials-today-chemistry/

Poly(amidoamine) dendrimers: covalent and supramolecular

synthesis
Z. Lyu a, L. Ding a, A.Y.-T. Huang a, b, C.-L. Kao b, c, L. Peng a, *
a
e, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, «Equipe Labellis

Aix-Marseille Universit
ee Ligue Contre le Cancer», 163 avenue
de Luminy, 13288 Marseille, France
b
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, 80708 Kaohsiung, Taiwan
c
Department of Medical Research, Kaohsiung Medical University Hospital, 100, Tzyou 1st Road, 807, Kaohsiung, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Dendrimers, a class of synthetic macromolecules which are notable for their well-defined ramified
Received 25 February 2019 structures and unique multivalent cooperativity, hold great promise for developing various functional
Received in revised form materials. Among all the reported dendrimers, poly(amidoamine) (PAMAM) dendrimers are the most
31 March 2019
extensively studied by virtue of their readily availability via robust synthesis as well as their dendritic
Accepted 5 April 2019
Available online 24 May 2019
structure and peptide/protein mimic features. Since the seminal report by Tomalia et al., various stra-
tegies have been made available for PAMAM dendrimers, including divergent and/or convergent syn-
thesis alongside click chemistry. Nevertheless, preparation of high-generation and defect-free PAMAM
Keywords:
Dendrimer synthesis
dendrimers on a large scale remains challenging. To overcome the limitations, an alternative strategy
Click chemistry based on self-assembling approach has emerged for dendrimer synthesis, where small dendritic com-
Self-assembling ponents form large non-covalent supramolecular structures that mimic high-generation covalent den-
Amphiphilic dendrimers drimers. This approach is easy to implement in practice and requires much less synthetic effort. Here, we
Supramolecular dendrimers present a brief overview of the different approaches established for PAMAM dendrimer synthesis. We
start with a general introduction to dendrimers and the common strategies for dendrimer synthesis, and
then we illustrate the specific approaches for PAMAM dendrimer synthesis and highlight the related
advantages and limitations using representative examples. Although various strategies have been
established for PAMAM dendrimer synthesis, innovative concepts and approaches are still in high
demand for reliably preparing defect-free and high-generation dendrimers in large quantity.
© 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).

1. Introduction
Dendrimers are a special family of synthetic polymers which
have a unique dendritic architecture characterized by regular
emanation of cascade-branched repeating units from a focal point
and a large number of end groups on the surface (Fig. 1) [1e4]. The
term ‘dendrimer’ was coined by chemists to describe molecules
with tree-like dendritic feature, and originated from the Greek
words ‘dendron’ and ‘mer’, which refer to ‘tree’ and ‘part’, respec-
tively [5,6]. By definition, dendrimers possess a well-defined
ramified structure consisting of three distinct parts: (1) a central
core, where a dendrimer growth begins; (2) repetitive branching
units, which allow for dendrimer growth in geometrically organized
* Corresponding author.
E-mail address: ling.peng@univ-amu.fr (L. Peng).
radial layers (named as generations); and (3) the numerous termi-
nal functionalities exposed on the surface (Fig. 1) [5]. These struc-
tural features make dendrimers distinctly different from traditional
linear, branched, and hyper-branched polymers and endow den-
drimers with unique functional properties and multivalent coop-
erativity confined within a small 3-dimensional space. Dendrimers
are therefore extremely appealing materials for a wide variety of
applications such as sensors, devices, catalysis, diagnostics, drugs,
and delivery systems in areas varying from environmental protec-
tion, energy production to human health.
Among all the dendrimers established, poly(amidoamine)
(PAMAM) dendrimers (Fig. 2) are the most extensively studied
ones. With a large number of amide and tertiary amine function-
alities in the interior and primary amine terminals on the surface,
the very first PAMAM dendrimers developed by Tomalia et al. were
originally envisioned to mimic proteins [5]. The peptide-mimicking
amide backbones along with numerous interior and terminal

https://doi.org/10.1016/j.mtchem.2019.04.004
2468-5194/© 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
 Z. Lyu et al. / Materials Today Chemistry 13 (2019) 34e48
Fig. 1. Cartoon illustration of the structure of a dendrimer composed of a central core,
the repetitive branching units which form the generations, and the terminal groups on
the dendrimer surface. The central core itself is generation 0 (G0); generation 1 (G1),
generation 2 (G2), and generation 3 (G3) refer to dendrimers with the first, second, and
third levels of branching, respectively. Reproduced with permission of Springer from
Ref. [80].
Fig. 2. Chemical structure of a 3rd generation of poly(amidoamine) (PAMAM) dendrimer bearing a triethanolamine-core [16].
35
amine functionalities make PAMAM dendrimers highly suitable for
biological applications when compared with other dendrimers
[7e15]. Nowadays, various PAMAM dendrimers with different
cores, branching units, and terminal groups have been devised and
constructed for a wide range of applications. In addition to their
dendritic properties and peptide/protein mimic features, the
popularity of PAMAM dendrimers in various studies and applica-
tions stems from their availability via reliable synthesis, with some
PAMAM dendrimers being commercially available at affordable
price. The first PAMAM dendrimer synthesis method developed by
Tomalia et al. [5,6] is still widely used and practiced today, although
other synthetic approaches have since been explored. It should
nevertheless be mentioned that the synthesis of high-generation
and defect-free PAMAM dendrimers on a large scale is still chal-
lenging. Below, we will present the different strategies for den-
drimer synthesis in general. We will then showcase PAMAM
dendrimer synthesis in particular using selected representative
examples, and we will comment on their relative virtues and
limitations.
2. Dendrimer synthesis
To undertake studies on dendrimers and successfully imple-
ment them in various applications, it is important that they are
readily available in the desired quantity and with consistent quality.
Unlike conventional polymers which are often prepared via ‘one-
pot’ synthesis, dendrimers are constructed via stepwise synthesis,
36 Z. Lyu et al. / Materials Today Chemistry 13 (2019) 34e48
which endows them with well-controlled structures and narrow
polydispersity. Dendrimer synthesis can be achieved using diver-
gent or convergent approaches or a combination of both (Fig. 3)
[1,3,4,17]. The divergent strategy involves construction of the den-
drimer from a multifunctional core which is extended outward by a
series of repetitive reactions (Fig. 3A). In contrast, in the convergent
strategy, dendrimers are built from small molecules that start at the
dendrimer surface and eventually end up attached to a central core
through a series of inward-oriented reactions (Fig. 3B) [18].
Using the divergent approach, dendrimers can be synthesized
up to generation 10 or even more. However, structural defects are a
critical concern for the synthesis of high-generation dendrimers
because they inevitably arise from incomplete reactions or side-
reactions that occur because of the increasing number of re-
actions and steric hindrance as the dendrimer grows [17]. In
addition, dendrimers with structural defects are often extremely
difficult to separate from intact dendrimers because of their similar
chemical compositions and physical properties. In contrast, using
the convergent approach, we can have much better control over
dendrimer synthesis, hence reducing or even suppressing struc-
tural defects. Also, impurities generated during convergent
synthesis can be easily separated as these impurities are usually
very different from the synthesized dendrimers in size, structure,
and physical properties. However, the reactivity to reach the inte-
rior core is often considerably reduced because of the increasing
steric congestion as the dendrimer generation increases. Therefore,
only low-generation dendrimers can be successfully prepared us-
ing the convergent method.
A combined divergent/convergent approach, also called the
double-stage convergent approach (Fig. 3C), has been further
developed and applied for dendrimer synthesis to combine the
advantages of divergent and convergent synthesis [18,19]. This
approach involves the synthesis of building blocks using a
Fig. 3. Cartoon presentation of the different approaches for covalent dendrimer synthesis: (A) the divergent approach, (B) the convergent approach, and (C) the combined divergent
and convergent approach.
divergent approach followed by the convergent dendrimer as-
sembly. In addition, the number of reaction steps required for
dendrimer synthesis and purification can be reduced, making the
preparation of higher generation dendrimers more efficient
compared with either divergent or convergent synthesis [17].
Another advantage of this approach is the ability to modify the
building blocks during dendrimer synthesis, thus endowing the
dendrimers with structural diversity.
High yield and completion of each individual reaction at each
synthetic step is crucial to maintain the purity and consistency of a
dendrimer. ‘Click chemistry’, by virtue of its high yield, high effi-
ciency, high atom economy, short reaction time, and mild reaction
conditions [20], has emerged as a popular approach for preparing
various dendrimers [21e24]. Successful implementation of click
chemistry has been achieved in dendrimer synthesis using the
divergent, convergent, or combined divergent/convergent
approach. In addition, great strides have been made in using click
chemistry to deliver simplified and accelerated dendrimer syn-
thesis yet with diverse structural complexity.
Historically, the first dendritic structures, also called ‘cascade
molecules’, were fabricated using divergent synthesis by Vo € gtle
et al. in 1978 (Fig. 4A) [25]. Although these molecules were small,
they marked the beginning of the concept of dendritic molecules. In
1985, Tomalia et al. reported the divergent synthesis of
PAMAM dendrimers, the first complete dendrimer family synthe-
sized from generation 1 to 7 (Fig. 4B), with molecular weights
reaching over 50000 Da [5]. This seminal work spurred unprece-
dented interest among the scientific community in all aspects of
dendrimer science including chemical synthesis, structural char-
acterization, functional evaluation, and various applications. Later,
Fre
chet et al. performed the first convergent synthesis of a family of
poly(arylether) dendrimers [26,27]. Soon after, they further estab-
lished a combined divergent/convergent approach for dendrimer
 Z. Lyu et al. / Materials Today Chemistry 13 (2019) 34e48 37

Fig. 4. Examples of different dendrimers: (A) ‘cascade molecule’ [25], (B) poly(arylether) dendrimer [19], (C) triazine dendrimer [37], (E) polylysine dendrimer [36], (D) NH3-core
PAMAM dendrimer [5], and (F) phosphorus dendrimer [38]. PAMAM, poly(amidoamine).

synthesis [19]. This double-stage convergent approach combined
the advantages of both divergent and convergent methods to
deliver accelerated dendrimer synthesis with structural diversity.
In 2004, the first example of dendrimer synthesis using click
chemistry was reported [24]. Since then, click chemistry has made
an important contribution to dendrimer synthesis thanks to its
high yield, simplicity, and rapidity, as well as its capacity for
structural diversity. Today, a wide variety of dendrimers have been
created and reported. These include peptide dendrimers, polyester
dendrimers, polyamine dendrimers, polyether dendrimers,
carbohydrate dendrimers, triazine dendrimers, carbosilane den-
drimers, and phosphorus dendrimers (Fig. 4) [28e36]. Collectively,
the reported dendrimers possess remarkable structural and
chemical diversity.
In contrast to the methods listed above for covalent dendrimer
synthesis, an alternative concept has recently emerged to advance
dendrimer synthesis through the self-assembly of small dendritic
components into large non-covalent supramolecular dendrimers
(Fig. 5) [39e43]. In the self-assembling process, supramolecular
structures can be created in a reversible yet modular and

Fig. 5. Cartoon presentation of the self-assembly approach for the synthesis of a non-covalent supramolecular dendrimer to mimic the covalent high-generation dendrimer [43].
Reproduced with permission of Wiley-VCH from Ref. [43].
38 Z. Lyu et al. / Materials Today Chemistry 13 (2019) 34e48

Fig. 6. Divergent synthesis of ammonia core PAMAM dendrimers via the iterative two-reaction sequences consisting of Michael addition and subsequent amidation [5,6]. PAMAM,
poly(amidoamine).

Fig. 7. Commercially available PAMAM dendrimers with different cores and terminal functions [51e54]. PAMAM, poly(amidoamine).
 Z. Lyu et al. / Materials Today Chemistry 13 (2019) 34e48 39

Fig. 8. Possible structural defects generated by the different side-reactions in PAMAM dendrimer synthesis. PAMAM, poly(amidoamine).

controlable way via multiple non-covalent interactions among
small building units. Of particular interest is that the self-
assembled structures can have completely new properties which
are distinct from those of the component molecules [44]. Therefore,
self-assembly is a promising approach in modern molecular science
for the creation of new materials [45e47]. Self-assembling supra-
molecular dendrimer construction has offered ever simplified and
cost-effective synthesis of dendrimers with completely new prop-
erties [39e43,48,49]. The concept of self-assembly of supramolec-
ular dendrimers is new, and the synthesis is easy to perform in
practice. It is therefore extremely appealing and offers a fresh input
into dendrimer synthesis and the related applications.
3. PAMAM dendrimer synthesis
As we have mentioned in the introduction, PAMAM dendrimers
are the most extensively investigated dendrimers for a wide range
of applications including molecular devices, sensors, catalysts,
drugs, diagnostics, drug-delivery vehicles, etc. PAMAM dendrimers
are widely used because they are readily synthesized [50]. Below,

Fig. 9. HPLC chromatogram of as-received PAMAM dendrimer of generation 5 from a commercial source [56]. PAMAM, poly(amidoamine). HPLC, hihg-performance liquid chro-
matography. Reproduced with permission of Elsevier from Ref. [56].
40 Z. Lyu et al. / Materials Today Chemistry 13 (2019) 34e48

Fig. 10. Convergent synthesis of PAMAM dendrimers using peptide synthesis chemistry [61]. PAMAM, poly(amidoamine).

we will illustrate the different approaches explored and established
for PAMAM dendrimer synthesis. These approaches encompass not
only covalent dendrimer synthesis using divergent and convergent
synthesis alongside click chemistry but also supramolecular den-
drimer construction via self-assembly. It is worth noting that
PAMAM dendrimers can be also prepared using solid-phase syn-
thesis in addition to the conventional solution-phase synthesis. We
will present PAMAM dendrimer synthesis using representative
examples of covalent synthesis, supramolecular synthesis, and
synthesis on a solid support. For each method, we will comment on
the advantages and restrictions related to dendrimer synthesis in
general and PAMAM dendrimers in particular.
3.1. Covalent synthesis
3.1.1. Solution synthesis
3.1.1.1. Divergent synthesis. In 1985, Tomalia et al. reported the first
PAMAM dendrimer synthesis using a divergent approach, involving
an iterative two-reaction sequence consisting of Michael addition
and amidation (Fig. 6) [5,6]. Their synthesis started with an amine-
 Z. Lyu et al. / Materials Today Chemistry 13 (2019) 34e48
Fig. 11. Convergent synthesis of PAMAM dendrimers involving click chemistry [62]. (A) Divergent synthesis of PAMAM dendrons bearing the alkyne functionality; (B) convergent
synthesis of symmetrical and asymmetrical PAMAM dendrimers using click chemistry. PAMAM, poly(amidoamine).
bearing core such as NH3 or ethylenediamine (EDA), which
underwent Michael addition with methyl acrylate to generate
ester-terminated dendrimers, also referred to as the half-
generation of PAMAM dendrimers. Subsequent amidation of the
ester-terminated dendrimers using ethylenediamine yielded the
amine-terminated PAMAM dendrimers. The overall synthesis of
PAMAM dendrimers was performed under very mild conditions,
using a large excess of methyl acrylate in the Michael addition and
ethylenediamine in the amidation reaction, which allowed the
corresponding dendrimers to be obtained with high yields. The
remaining excess methyl acrylate and ethylenediamine were
removed conveniently in vacuo because both of them are relatively
volatile. Further purification procedures such as precipitation and
dialysis were also applied to purify the ester-terminated and
amine-terminated PAMAM dendrimers, respectively. By repeating
these synthesis/purification procedure cycles, higher generations of
both the ester-terminated and amine-terminated PAMAM den-
drimers were obtained, with generations up to 7 [5].
It is worth noting that the ester-terminated PAMAM dendrimers
can be further subjected to hydrolysis to deliver the corresponding
carboxylic acideterminated dendrimers. Alternatively, by replacing
ethylenediamine with ethanolamine in the amidation step,
hydroxyl-terminated PAMAM dendrimers can be synthesized. Fig. 7
illustrates the commercially available PAMAM dendrimers with
different cores and terminal groups [51e54]. The functional ter-
minals, such as amine, hydroxyl, and carboxylic acid groups, can be
further modified or conjugated easily to yield various PAMAM
dendrimer conjugates with desired properties and functions for
diverse applications.
Despite highly efficient synthesis of PAMAM dendrimers using
Tomalia's method, multiple structural defects can result from
various side-reactions such as incomplete Michael addition, retro-
Michael reaction, intramolecular cyclization, and/or dimerization
during amidation (Fig. 8) [5,6,55]. Incomplete Michael reaction
yields dendrimers with missing branching arms, whereas the close
41
proximity of the terminal groups and the dendrimer molecules
gives rise to intramolecular cyclization and intermolecular dimer-
ization during the amidation step. Also, retro-Michael reaction is a
common problem at elevated temperatures (>60
C), although it
can be reduced considerably by using a reaction temperature below
60
C. As a consequence of the retro-Michael reaction, a branching
chain is cleaved, and a defective dendrimer with one missing
branch is formed. The resulting defective dendrimer is able to un-
dergo further Michael addition with ethylenediamine to generate
additional defective dendrimers.
In the case of PAMAM dendrimers, defects occur inevitably
beyond generation 4 because of structural crowding. Very often,
the defective dendrimers are difficult to separate from the intact
dendrimers because of their similar chemical compositions and
physicochemical properties. Fig. 9 shows the HPLC chromatogram
at 210 nm of as-received G5 dendrimer from a commercial source
[56]. It highlights the presence of trailing generation impurities as
well as oligomerization defects.
Many applications require high-purity dendrimers, in particular
biomedical applications [50]. It should be mentioned that den-
drimer defects have been implicated in the failure of a significant
preclinical trial focused on the development of dendrimer-based
targeted delivery of an anticancer drug [57,58]. Therefore, special
attention should be paid to the dendrimer synthesis and the related
purification process. It is advisable to verify the purity of the
commercially available PAMAM dendrimers [59] and further purify
them via dialysis or preparative high-performance liquid chroma-
tography when the dendrimer purity is a concern [56,60]. Conse-
quently, the synthesis of high-generation and defect-free PAMAM
dendrimers on a large scale is by no means trivial and constitutes a
highly demanding technical challenge.
3.1.1.2. Convergent synthesis. Besides divergent synthesis of
PAMAM dendrimers, Christensen et al. applied the convergent
approach to construct PAMAM dendrimers (Fig. 10) [61]. They
42 Z. Lyu et al. / Materials Today Chemistry 13 (2019) 34e48

Fig. 12. Examples of (A) a Janus dendrimer [78], (B) an amphiphilic dendrimer [69] and (C) a bola-amphiphilic dendrimer [67] synthesized using the convergent approach in
combination with click chemistry.
 Z. Lyu et al. / Materials Today Chemistry 13 (2019) 34e48
Fig. 13. Solid-phase synthesis of PAMAM dendrimers via iterative Michael addition and amidation [70]. PAMAM, poly(amidoamine).
first prepared PAMAM dendrons from generation 1 to 3 using the
divergent approach via iterative amide bond formation and
amine-deprotection. This reaction sequence was completely
different from Tomalia's synthesis yet widely used in peptide
synthesis. The obtained amine-bearing dendrons were then
coupled with the dendrimer core harboring four carboxylic acid
terminals to deliver the corresponding PAMAM dendrimers.
Because of the steric hindrance generated in the convergent
synthesis with high-generation dendrons, only dendrimers up
to generation 4 could be prepared using this method. This is far
lower than the dendrimers prepared using the classical divergent
method developed by Tomalia.
Lee et al. further established convergent synthesis by taking
advantage of click chemistry to assemble PAMAM dendrimers
(Fig. 11) [62,78,79]. PAMAM dendrons bearing the alkyne func-
tionality were prepared first in high yield using the classic diver-
gent method developed by Tomalia (Fig. 10A). Subsequent
conjugation with azide-bearing cores via click chemistry offered
43
either symmetrical or asymmetrical PAMAM dendrimers by as-
sembly of either the same or the different dendrons, respectively
(Fig. 10B). Also, only dendrimers up to generation 4 could be pre-
pared because of the steric congestion created in high-generation
dendrons. It is worth noting that click chemistry in combination
with convergent synthesis has been then widely applied to prepare
various Janus dendrimers, amphiphilic dendrimers, and bola-
amphiphilic dendrimers [63e68]. Fig. 12 illustrates some repre-
sentative examples of such PAMAM dendrimers.
3.1.2. Solid-phase synthesis
Apart from solution synthesis, solid-phase synthesis has been
also applied to construct PAMAM dendrimers (Fig. 13) [70]. Bradley
et al. explored solid-phase synthesis of PAMAM dendrimers by
making use of the same chemistry developed by Tomalia for solu-
tion synthesis, namely, the iterative reaction sequence consisting of
Michael addition and amidation. In this way, they obtained PAMAM
dendrimers up to generation 4 on a solid support [70]. Bradley et al.
44 Z. Lyu et al. / Materials Today Chemistry 13 (2019) 34e48
Fig. 14. Solid-phase synthesis of PAMAM dendrimers using peptide synthesis chemistry [73]. PAMAM, poly(amidoamine); TFA, trifluoroacetic acid; PyBOP, (Benzotriazol-1-yloxy)
tripyrrolidinophosphonium hexafluorophosphate.
proposed that the dendrimer-functionalized solid supports could
be used as super high-loading reagents for solid-phase synthesis
[71,72]. By virtue of their multivalency, dendrimer-modified solid
supports provide more reactive sites and allow more reactions to
occur simultaneously when compared with the conventional
solid-phase support [71].
Huang et al. established an ingenious and concise solid-phase
synthesis method for PAMAM dendrimers by harnessing peptide
synthesis chemistry (Fig. 14) [73]. Using a branching unit which
harbors both carboxylic acid and amine terminals, PAMAM den-
drimers were synthesized via iterative amide bond formations un-
der the classical peptide synthesis conditions for solid-phase
synthesis (Fig. 14). In contrast to the conventional PAMAM synthesis
using the two-step iterative protocol consisting of Michael addition
and amidation, the peptide synthetic approach significantly short-
ened the reaction steps, simplified the product purification, and at
the same time, prevented the structural defects originating from
Michael addition and amidation. This highly efficient protocol was
carried out both manually and automatically using a solid-phase
peptide synthesizer, enabling synthesis of dendrimers up to gener-
ation 7 [74]. Despite all these beneficial advantages, solid-phase
dendrimer synthesis has not yet been widely used in practice. This
is mainly because the production of dendrimers in the desired large
quantities is still a challenging task for solid-phase synthesis.
It is worth mentioning that the PAMAM dendrimers prepared
using the peptide synthesis strategy by Huang et al. have the amide
bond linkage in the opposite direction [73] compared with the
conventional PAMAM dendrimers synthesized using Tomalia's
procedure (Fig. 15). Therefore, these dendrimers are also referred to
as inverse PAMAM dendrimers. Also of note is that these inverse
PAMAM dendrimers have one more methylene unit in the diamine
connecting unit than the conventional PAMAM dendrimers ob-
tained using Tomalia's method [73]. This longer diamine unit is able
to prevent the self-cyclization side-reaction during dendrimer
growth, and it also ensures that the inverse PAMAM dendrimers are
similar in size to the PAMAM dendrimers prepared using Tomalia's
approach.
3.2. Supramolecular synthesis
Self-assembly of small dendritic components into large non-
covalent supramolecular dendrimer systems is a practical and
cost-effective approach to create large dendrimers. This is because
the cumulative effects of multiple non-covalent interactions allow
the assembly of small dendritic building blocks into large supra-
molecular dendrimers in a reversible and controllable way, which
can be harnessed to establish specially designed functional mate-
rials. For example, we have recently established supramolecular
dendrimers using various self-assembling small amphiphilic den-
drimers which bear long hydrophobic alkyl chains and small
hydrophilic PAMAM dendrons (Fig. 16) [43,49,64,65,67,69,75,76].
The synthesis of the small amphiphilic dendrimers was achieved
via click chemistry by convergent coupling of the hydrophobic core
with hydrophilic PAMAM dendrons obtained by the divergent
approach using Tomalia's method [49,64e66,69]. The obtained
amphiphilic dendrimers were able to form stable, spherical,
 Z. Lyu et al. / Materials Today Chemistry 13 (2019) 34e48 45

Fig. 15. (A) A PAMAM dendrimer synthesized in the solid phase using the peptide synthesis strategy has the amide bond linkage in the opposite direction compared to (B) a PAMAM
dendrimer prepared using the conventional two-reaction procedure [73]. PAMAM, poly(amidoamine).

nanoscale supramolecular dendrimers. These non-covalently con-
structed dendrimers can be readily controlled and modulated in
size and shape by varying the length of the hydrophobic chain and/
or the generation of the hydrophilic PAMAM dendron [43,49,75].
Importantly, the supramolecular dendrimers can mimic the
covalently constructed high-generation dendrimers for drug de-
livery and bioimaging. For example, the large void space in the
hydrophobic interior was harnessed to encapsulate the anticancer
drug doxorubicin with high loading capacity (Fig. 17). This effec-
tively enhanced the potency of the drug and reduced the drug
resistance by promoting cellular uptake and decreasing drug efflux
[75]. The amphiphilic dendrimers could also be chemically conju-
gated with multiple copies of a bioactive molecule [66] or an
imaging functionality [49] at the PAMAM terminals to construct
self-assembling supramolecular dendrimers for drug delivery and
bioimaging, respectively. It is worth noting that the self-assembled
supramolecular dendrimer shown in Fig. 16B, which was developed
for positron emission tomography imaging, accumulated in tumors
via passive tumor targeting mediated by the ‘enhanced perme-
ability and retention (EPR)’ effect [49]. This supramolecular den-
drimer, which benefited from both dendrimeric multivalence and
EPR-mediated passive tumor targeting, demonstrated superior
sensitivity and specificity for tumor imaging when compared with
the clinical golden reference, [18F] FDG (2-fluorodeoxyglucose).
It should also be mentioned that the large number of terminal
amine groups on the surface of supramolecular PAMAM den-
drimers are positively charged at physiological pH, and hence can
interact with negatively charged nucleic acids to form stable and

Fig. 16. Supramolecular dendrimers constructed via self-assembly of small amphiphilic dendrimers bearing (A) a hydrophobic C18 alkyl chain and a hydrophilic PAMAM dendron
with 8 amine-terminals for nucleic acid delivery [43] Reproduced with permission of Wiley -VCH from Ref. [43] and (B) a hydrophobic C18 alkyl chain and a hydrophilic PAMAM
dendron with 4 terminals carrying the radioactive Ga/NOTA-entities for PET imaging of tumors [49]. Reproduced with permission of PNAS from Ref. [49]. PET, positron emission
tomography. PAMAM, poly(amidoamine).
46 Z. Lyu et al. / Materials Today Chemistry 13 (2019) 34e48

Fig. 17. Self-assembled supramolecular PAMAM dendrimers for drug delivery by physical encapsulation of drug molecules within the interior [75]. PAMAM, poly(amidoamine).
Reproduced with permission of PNAS from Ref. [77].

compact nanoscale dendriplexes for nucleic acid delivery (Fig. 18)
[43,65]. Some of these supramolecular PAMAM dendrimers even
outperformed the currently existing vectors for functional delivery
of small interfering RNA, and one of the dendrimers has been
scheduled for preclinical and clinical studies [77]. Further decora-
tion on the surface of the formed dendriplexes with a targeting
peptide resulted in targeted and specific delivery, leading to much
better delivery efficiency [76]. Collectively, these studies
demonstrate that construction of non-covalent supramolecular
dendrimers using the self-assembly approach provides a new
perspective for creating functional dendrimers with novel and
promising properties. We foresee that this self-assembly approach
may transform dendrimer synthesis in general and give a fresh
boost to the various applications of PAMAM dendrimers as well as
other dendrimers.

Fig. 18. Exploiting the positively charged amine terminals of self-assembled supramolecular PAMAM dendrimers to compact negatively charged nucleic acid molecules for nucleic
acid delivery [43,65,76]. siRNA, small interfering RNA; PAMAM, poly(amidoamine). Reproduced with permission of Wiley-VCH from Ref. [65].
 Z. Lyu et al. / Materials Today Chemistry 13 (2019) 34e48
4. Concluding remarks
In this short review, we have presented various approaches for
synthesizing PAMAM dendrimers, the most extensively studied
dendrimer class. The applications of PAMAM dendrimers in various
fields are largely because of their ready availability and peptide/
protein mimic features in addition to their well-defined dendritic
structures and intrinsically generated multivalent cooperativity.
PAMAM dendrimers can be readily prepared using the iterative
reaction sequence developed by Tomalia and are easily conjugated
with various functionalities. Importantly, some PAMAM den-
drimers are commercially available at an affordable price. There-
fore, the study of PAMAM dendrimers has flourished, and they have
been widely implemented in various applications ranging from
molecular devices, sensors, and catalysts to drugs and drug-
delivery systems.
Despite the procedures established by Tomalia et al. and the
availability of alternative approaches using divergent and/or
convergent synthesis in combination with click chemistry, the
synthesis of high-generation and defect-free PAMAM dendrimers
on a large scale remains a great challenge. The major obstacles
include tedious synthesis accompanied by inevitable structural
defects and laborious purification. To overcome these limitations,
solid-phase synthesis of PAMAM dendrimers has been developed,
using either the same chemistry developed by Tomalia or the
chemistry stemming from peptide synthesis. However, the prac-
tical utility and applications of solid-phase dendrimer synthesis
have not yet been fully exploited and approved, in contrast to solid-
phase peptide synthesis, which is well established for achieving
reliable synthesis of any peptide. We expect continuous interest
and engagement in this direction, which will improve solid-phase
chemistry for the convenient and efficient synthesis of high-
generation and defect-free dendrimers with widely applicable
chemistry and structural diversity.
Self-assembly of small and easily synthesized dendritic com-
ponents into large supramolecular dendrimers has recently
emerged as a completely new concept for dendrimer construc-
tion. Supramolecular dendrimers can be easily adapted and
modulated to generate the desired properties and functions yet
with relatively little synthetic effort. This approach has been
successfully applied to create non-covalent dendrimers which
can mimic covalently constructed high-generation PAMAM den-
drimers for nucleic acid and drug delivery. Some of them have
proved to be greatly superior to the current lipid and polymer
delivery systems. Compared with other polymers and den-
drimers, PAMAM dendrimers have many outstanding character-
istics that make them highly suitable for biological applications,
including their peptide-mimicking amide backbones and their
numerous interior and terminal amine functionalities. The ad-
vantageous features of supramolecular PAMAM dendrimers,
together with their easy synthesis and implementation, hold
great promise for various applications in many different fields.
Advances in cost-effective synthesis of defect-free and high-
generation dendrimers on a large scale are still of paramount
importance and will be a key driving force for the practical
implementation of dendrimers in serving and benefiting our
society. Scientists with dedication and strong determination are
actively working in this direction.
Acknowledgements
This work was supported by the Ligue Nationale Contre le
Cancer (LP, ZL), the international ERA-Net EURONANOMED Euro-
pean Research projects ‘Target4Cancer’, ‘NANOGLIO’, and ‘TAR-
BRAINFECT’ (LP), H2020 NMBP ‘SAFE-N-MEDTECH’ (LP), Project
47
PHC ORCHID (LP, CLK), China Scholarship Council (LD), Bourse
d’Excellence Eiffel (AYTH), Overseas Training Abroad Scholarship
from Taiwan (AYTH), the Ministry of Education of Taiwan,
the Ministry of Science and Technology of Taiwan, the CNRS,
Aix-Marseille University, and Kaohsiung Medical University. The
authors are grateful to Isabel Hansel for English correction.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.mtchem.2019.04.004.
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